CN104672093A - Method for preparing dicyclopropane methyl amine - Google Patents
Method for preparing dicyclopropane methyl amine Download PDFInfo
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- CN104672093A CN104672093A CN201510124043.5A CN201510124043A CN104672093A CN 104672093 A CN104672093 A CN 104672093A CN 201510124043 A CN201510124043 A CN 201510124043A CN 104672093 A CN104672093 A CN 104672093A
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Abstract
The invention relates to a method for preparing dicyclopropane methyl amine. The method comprises a step of performing catalytic hydrogenation on the dicyclopropane ketoxime and the hydrogen under the existence of a catalyst to generate the dicyclopropane methyl amine, wherein the raney nickel is taken as a catalyst in the catalytic hydrogenation and the process is performed in the water or the alkaline solution at the temperature of 30-90 DEG C. Compared with the current hydrogenation, the method has the advantages that a high-purity product with obviously increased yield can be obtained, the salt formation and dissociation process in an alcohol solvent can be avoided and the operation can be greatly simplified, besides, the costs of the solvent and the post-processing solvent can be greatly reduced, the wastewater discharge can be reduced and the process is green and environmentally friendly.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, be specifically related to the preparation method of bicyclo-propyl methylamine.
Background technology
Bicyclo-propyl methylamine is the important intermediate of depressor rilmenidine, is widely used in the synthesis of medicine.The synthetic method of traditional bicyclo-propyl methylamine mainly comprises two steps, first generates oxime intermediate by bicyclo-propyl ketone and oxammonium hydrochloride generation oximation reaction, then obtains bicyclo-propyl methylamine by oxime intermediate generation hydrogenation.Reported oximation reaction carries out being obtained by reacting of long period usually under alkali such as sodium bicarbonate and high temperature.Such as CN1629144A discloses and makes bicyclo-propyl ketone and oxammonium hydrochloride in water, and sodium bicarbonate prepares oxime intermediate in 8 hours in 150 DEG C of insulation reaction under existing, and yield is 71%.Reported hydrogenation mainly contains two kinds, a kind of employing sodium Metal 99.5/ethanol reduction system, another kind of employing Raney's nickel/hydrogen/alcohol catalysis hydrogenation system (see CNCN1629144A), after hydrogenation terminates, make bicyclo-propyl methylamine become phos-phate forms to separate out, then dissociate with potassium hydroxide, then through layering, add solid potassium hydroxide dehydration, distillation obtains bicyclo-propyl methylamine.The former yield is very low, only be about 25%, and the application of sodium Metal 99.5, potential safety hazard is large, although and the crude yield of the latter's report is relatively high, reach 75%, but complex steps, aftertreatment is complicated, and will consume a large amount of dehydrated alcohols and produce a large amount of waste liquids, and having water-soluble due to bicyclo-propyl methylamine, hierarchical operations is actually unrealistic.
CN102353710 discloses the route that a kind of high temperature one step generates bicyclo-propyl methylamine, it makes bicyclo-propyl ketone and ammonium formiate at 160-170 DEG C, long-time back flow reaction generates bicyclo-propyl methylamine, although this route saves processing step, but there is following deficiency: 1) require very high to appointed condition, energy consumption is large, and 2) because the rigidity of cyclopropyl rings is very large, unavoidably has triatomic ring open loop side reaction under the high temperature conditions and occur; 3) high temperature also can cause the partial oxidation of ketone, makes product partially assorted; 4) bicyclo-propyl propylamine has water-soluble, washes excessive ammonium formate with water in its patent, unavoidably will large-tonnage product be washed in solution, cause yield on the low side.
Summary of the invention
Technical problem to be solved by this invention overcomes the deficiencies in the prior art, provides a kind of preparation method of bicyclo-propyl methylamine of improvement.
For solving above technical problem, the technical scheme that the present invention takes is as follows:
A kind of preparation method of bicyclo-propyl methylamine, it comprises bicyclo-propyl ketoxime and hydrogen are occurred in the presence of a catalyst step that catalytic hydrogenation generates bicyclo-propyl methylamine, wherein catalytic hydrogenation adopts Raney's nickel to be catalyzer, carries out in water or in alkaline aqueous solution and at temperature 30-90 DEG C.
Preferably, catalytic hydrogenation is carried out in alkaline aqueous solution.
Preferably, alkaline aqueous solution is one or more the aqueous solution be selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate.
Preferably, described catalytic hydrogenation is carried out at temperature 60-80 DEG C.
Further, catalytic hydrogenation is made to carry out under pressure 1-4Mpa.Preferably, catalytic hydrogenation is made to carry out under pressure 2-3Mpa.
Concrete and the preferred aspect according to one of this invention, described catalytic hydrogenation is implemented as follows: joined by reaction desired raw material in high-pressure hydrogenation still, after nitrogen replacement, pass into hydrogen, control the temperature in hydriding reactor, react, react complete, discharging, cooling, cross and filter Raney's nickel, then use dichloromethane extraction, extracting solution distills, and collects 100mmHg, the cut of 100-110 DEG C, is bicyclo-propyl methylamine.
Further, the inventive method also comprises makes bicyclo-propyl ketone and oxammonium hydrochloride in the presence of a base, the step that oximation reaction generates bicyclo-propyl ketoxime occurs in water, and carry out described catalytic hydrogenation reaction again after being extracted from the product system that described oximation reaction obtains by bicyclo-propyl ketoxime, or, the product system that described oximation reaction obtains is directly used in next step catalytic hydrogenation reaction.
Preferably, oximation reaction is made to carry out at temperature 50-80 DEG C.React not only that energy consumption of reaction is relatively low at such a temperature, and the yield of bicyclo-propyl ketoxime is greater than 85%.
Further, described alkali is not particularly limited, such as can for being selected from one or more the combination in sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate.
Preferably, when carrying out described oximation reaction, bicyclo-propyl ketone and oxammonium hydrochloride are added to the water, stirring and dissolving, then drips the aqueous solution of described alkali, and in the process of dropping, hierarchy of control temperature is lower than 50 DEG C, and drip and finish, control temperature reacts; Or be added to the water by oxammonium hydrochloride, stirring and dissolving, then drips the aqueous solution of described alkali, and in the process of dropping, hierarchy of control temperature is lower than 50 DEG C, drip and finish, drip bicyclo-propyl ketone, drip and finish, control temperature reacts.
According to a specific embodiments of the present invention, oxammonium hydrochloride is added to the water, stirring and dissolving, then drip the aqueous solution of sodium hydroxide, in the process of dropping, hierarchy of control temperature is lower than 50 DEG C, drips and finishes, drip bicyclo-propyl ketone, drip and finish, control temperature 50-55 DEG C reacts.Take this kind of embodiment, the yield of bicyclo-propyl ketoxime is greater than 90%.
Owing to taking above technical scheme, the present invention compared with prior art tool has the following advantages:
The present invention makes the catalytic hydrogenation reaction of employing Raney's nickel and hydrogen carry out in water or in alkaline aqueous solution, compared with the hydrogenation reported with prior art, highly purified product can not only be obtained with the yield significantly improved, and the salify can avoiding carrying out in alcoholic solvent, the process such as to dissociate, greatly simplify operation, in addition, also significantly reduce the cost of solvent and post-treatment reagents, decrease discharge of wastewater, make technique environmental protection more.
Embodiment
In view of the various deficiencies in prior art existing for the preparation of bicyclo-propyl methylamine, the present invention, based on traditional two step reaction schemes, improves.Particularly, the present invention, reacts with oxammonium hydrochloride for starting raw material with bicyclo-propyl ketone in alkali aqueous solution, obtains bicyclo-propyl ketoxime; Then, the oxime system obtained can carry out after aftertreatment extracts oxime, carrying out next step catalytic hydrogenation reaction, also without aftertreatment, and can being directly used in next step shortening solid/liquid/gas reactions.After catalytic hydrogenation reaction, with dichloromethane extraction, dry, obtain the dichloromethane solution of bicyclo-propyl amine; Then distill, collect the cut of 100mmHg, 100-110 DEG C, be the main distillate fraction of bicyclo-propyl methylamine, purity is between 98.5-99.7%, and total recovery can reach more than 87%.
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the invention is not restricted to following examples.In embodiment, not marked condition is the condition of this area routine.
embodiment 1oximation reaction prepares bicyclo-propyl ketoxime
Get bicyclo-propyl ketone 110g, and oxammonium hydrochloride (77g), add 200ml water, stirring and dissolving.Then drip the sodium bicarbonate aqueous solution 500ml of 10wt%, control temperature, lower than 50 DEG C, dropwises for about 20 minutes.Then be warmed up to 60-80 DEG C, stir about 2 hours, reacts complete.In reaction process, separate out white solid, then cool to 0-5 DEG C, stir 2 hours, white solid is separated out in a large number.Suction filtration, dries, obtains bicyclo-propyl ketoxime and be about 110g, yield about 88%.
1hNMR (Jeol, 400MHz, CDCl
3) data are as follows: δ 0.60ppm (m, 4H, 2CH2); δ 0.86ppm (m, 4H, 2CH2); δ 0.97ppm (m, 1H, CH); δ 2.40ppm (t, 1H, CH); δ 8.30ppm (s, 1H, OH).
embodiment 2oximation reaction prepares bicyclo-propyl ketoxime
Get oxammonium hydrochloride (77g), add 200ml water, stirring and dissolving.Then drip the sodium hydroxide 500ml of 10wt%, control temperature, lower than 50 DEG C, dropwises for about 20 minutes.Then drip 110g bicyclo-propyl ketone at 50 DEG C-55 DEG C, time for adding about 1.5 hours, then continue stir about 1 hour, react complete.In reaction process, separate out white solid, then cool to 0-5 DEG C, stir 2 hours, white solid is separated out in a large number.Suction filtration, dries, obtains bicyclo-propyl ketoxime and be about 115g, yield about 92%.
embodiment 3catalytic hydrogenation reaction prepares bicyclo-propyl methylamine
Bicyclo-propyl ketoxime 100g is added, Raney's nickel 6g, water 350ml in 500ml high-pressure hydrogenation still.Then nitrogen replacement 3 times, passes into hydrogen.Controlling reactor hydrogen pressure is 2Mpa, and temperature is 70-80 DEG C, after 4 hours, reacts complete.Discharging, cooling, mother liquor adds sodium hydroxide 10g, stirs, suction filtration, removing Raney's nickel.Then three times are extracted with methylene dichloride 200ml, combined dichloromethane solution, distillation.Collect the cut of 100mmHg, 100-110 DEG C, be product bicyclo-propyl methylamine.Obtain product altogether and be about 70g, yield 74.2%.
1hNMR (Jeol, 400MHz, DMSO-d6) data are as follows: δ 0.15ppm (m, 4H, 2CH2); δ 0.29ppm (m, 4H, 2CH2); δ 1.56ppm (t, 1H, CH); δ 5.74pp m (s, 2H, NH2).
embodiment 4catalytic hydrogenation reaction prepares bicyclo-propyl methylamine
Bicyclo-propyl ketoxime 100g is added, Raney's nickel 6g, water 350ml, sodium hydroxide 10g in 500ml high-pressure hydrogenation still.Then nitrogen replacement 3 times, passes into hydrogen.Controlling reactor hydrogen pressure is 2Mpa, and temperature is 70-80 DEG C, after 4 hours, reacts complete.Discharging, cooling, stirs, suction filtration, removing Raney's nickel.Then three times are extracted with methylene dichloride 200ml, combined dichloromethane solution, distillation.Collect the cut of 100mmHg, 100-110 DEG C, be product bicyclo-propyl methylamine.Obtain product altogether and be about 81g, yield 85.8%.
embodiment 5bicyclo-propyl methylamine is prepared in two step reactions
Oximation reaction: get oxammonium hydrochloride (77g), add 200ml water, stirring and dissolving.Then the sodium hydroxide 250ml of fast drop 20%, control temperature, lower than 50 DEG C, dropwises for about 20 minutes.Then drip 110g bicyclo-propyl ketone at about 50 DEG C, time for adding about 1.5 hours, then continue stir about 1 hour, react complete.
Catalytic hydrogenation reaction: directly added in 1L high-pressure hydrogenation still by oximation reaction products therefrom solution, add Raney's nickel 8g, then nitrogen replacement 3 times, passes into hydrogen.Controlling reactor hydrogen pressure is 3Mpa, and temperature is 50-60 DEG C, after 4 hours, reacts complete.Discharging, cooling, stirs, suction filtration, removing Raney's nickel.Then three times are extracted with methylene dichloride 200ml, combined dichloromethane solution, distillation.Collect the cut of 100mmHg, 100-110 DEG C, be product bicyclo-propyl methylamine.Obtain product altogether and be about 97g, yield 87.4%.
Bicyclo-propyl methylamine is prepared in the reaction of embodiment 6 two step
Oximation reaction: get oxammonium hydrochloride (77g), add 200ml water, stirring and dissolving.Then the sodium hydrogen carbonate solution 250ml of fast drop 20%, control temperature, lower than 50 DEG C, dropwises for about 20 minutes.Then drip 110g bicyclo-propyl ketone at about 50 DEG C, time for adding about 1.5 hours, then continue stir about 1 hour, react complete.
Catalytic hydrogenation reaction: directly added in 1L high-pressure hydrogenation still by oximation reaction products therefrom solution, add Raney's nickel 8g, then nitrogen replacement 3 times, passes into hydrogen.Controlling reactor hydrogen pressure is 1Mpa, and temperature is 50-60 DEG C, after 15 hours, reacts complete.Discharging, cooling, stirs, suction filtration, removing Raney's nickel.Then three times are extracted with methylene dichloride 200ml, combined dichloromethane solution, distillation.Collect the cut of 100mmHg, 100-110 DEG C, be product bicyclo-propyl methylamine.Obtain product altogether and be about 92g, yield 82.8%
Above to invention has been detailed description; its object is to allow the personage being familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence change that all spirit according to the present invention are done or modification, all should be encompassed in protection scope of the present invention.
Claims (10)
1. the preparation method of a bicyclo-propyl methylamine, it comprises bicyclo-propyl ketoxime and hydrogen are occurred in the presence of a catalyst step that catalytic hydrogenation generates bicyclo-propyl methylamine, it is characterized in that: described catalytic hydrogenation adopts Raney's nickel to be catalyzer, carries out in water or in alkaline aqueous solution and at temperature 30-90 DEG C.
2. the preparation method of bicyclo-propyl methylamine according to claim 1, is characterized in that: described alkaline aqueous solution is one or more the aqueous solution be selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate.
3. the preparation method of bicyclo-propyl methylamine according to claim 1, is characterized in that: described catalytic hydrogenation is carried out at temperature 60-80 DEG C.
4. the preparation method of bicyclo-propyl methylamine according to claim 1, is characterized in that: catalytic hydrogenation is carried out under pressure 1-4Mpa.
5. the preparation method of bicyclo-propyl methylamine according to claim 4, is characterized in that: catalytic hydrogenation is carried out under pressure 2-3Mpa.
6. the preparation method of the bicyclo-propyl methylamine any one of claim 1 to 5 described in claim, is characterized in that, described catalytic hydrogenation is implemented as follows: joined by reaction desired raw material in high-pressure hydrogenation still, after nitrogen replacement, pass into hydrogen, control the temperature in hydriding reactor, react, react complete, discharging, cooling, crosses and filters Raney's nickel, then use dichloromethane extraction, extracting solution distills, collect the cut of 100mmHg, 100-110 DEG C, be bicyclo-propyl methylamine.
7. the preparation method of bicyclo-propyl methylamine according to claim 1, it is characterized in that: described method also comprises makes bicyclo-propyl ketone and oxammonium hydrochloride in the presence of a base, the step that oximation reaction generates bicyclo-propyl ketoxime occurs in water, and carry out described catalytic hydrogenation reaction again after being extracted from the product system that described oximation reaction obtains by bicyclo-propyl ketoxime, or, the product system that described oximation reaction obtains is directly used in next step catalytic hydrogenation reaction.
8. the preparation method of bicyclo-propyl methylamine according to claim 7, is characterized in that: described oximation reaction is carried out at temperature 50-80 DEG C.
9. the preparation method of bicyclo-propyl methylamine according to claim 7, is characterized in that: described alkali is one or more the combination be selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate.
10. the preparation method of the bicyclo-propyl methylamine according to claim 7 or 8 or 9, it is characterized in that: when carrying out described oximation reaction, bicyclo-propyl ketone and oxammonium hydrochloride are added to the water, stirring and dissolving, then the aqueous solution of described alkali is dripped, in the process dripped, hierarchy of control temperature is lower than 50 DEG C, and drip and finish, control temperature reacts; Or be added to the water by oxammonium hydrochloride, stirring and dissolving, then drips the aqueous solution of described alkali, and in the process of dropping, hierarchy of control temperature is lower than 50 DEG C, drip and finish, drip bicyclo-propyl ketone, drip and finish, control temperature reacts.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115322082A (en) * | 2022-08-31 | 2022-11-11 | 郑州药领医药科技有限公司 | Preparation method of tetralone compound |
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| US4411925A (en) * | 1980-01-21 | 1983-10-25 | Pfizer Inc. | Branched amides of L-aspartyl-d-amino acid dipeptides |
| CN102351710A (en) * | 2011-10-21 | 2012-02-15 | 合肥工业大学 | Preparation method of medicine intermediate di-cyclopropyl methylamine |
| WO2015003360A2 (en) * | 2013-07-11 | 2015-01-15 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
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2015
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| US4411925A (en) * | 1980-01-21 | 1983-10-25 | Pfizer Inc. | Branched amides of L-aspartyl-d-amino acid dipeptides |
| CN102351710A (en) * | 2011-10-21 | 2012-02-15 | 合肥工业大学 | Preparation method of medicine intermediate di-cyclopropyl methylamine |
| WO2015003360A2 (en) * | 2013-07-11 | 2015-01-15 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
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| ADAM P. TREDER ET AL.: "New imidazoline/α2-adrenoceptors affecting compounds—4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115322082A (en) * | 2022-08-31 | 2022-11-11 | 郑州药领医药科技有限公司 | Preparation method of tetralone compound |
| CN115322082B (en) * | 2022-08-31 | 2024-02-23 | 郑州药领医药科技有限公司 | Preparation method of tetralone compound |
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